Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the Weill Cornell Medical College and Mount Sinai is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (7/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1100 9- 10 year olds enriched for high-risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 1 hubs across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This NYC site Research Project focuses on risk for and outcomes of substance use on adolescent brain and behavioral development. Our theoretically and empirically grounded aims build on the collective expertise at Weill Cornell, Mt. Sinai, Columbia University and Cornell Tech in adolescent brain development, addiction brain circuitry, and mobile technology for assessing substance use and health. The three aims are: 1) to examine how mismatches in development of prefrontal and subcortical regions relate to initiation and frequency of substance use based on the Imbalance Model of Adolescence; 2) to examine how substance abuse impacts prefrontal and subcortical development implicated in inhibitory control and motivational processes based on the Impaired Response Inhibition and Salience Attribution (iRISA) Model of Addiction; and 3) to examine how genetic variation in endocannabinoid signaling impacts initiation and frequency of substance use and underlying circuit development in humans, based on a knock-in mouse model that shows vertical integration from gene to circuit to behavior, filling a translational gap from mouse to human of potential therapeutic relevance for prevention and treatment of substance use disorders.